Steroid Regulation of Ion Channels

离子通道的类固醇调节

• 批准号: 6865492
• 负责人: LESLIE P HENDERSON
• 金额: $ 23.85万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865492
• 关键词: Steroid; Regulation; Ion; Channels

EXCEED THE SPACE PROVIDED. Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone developed for hypogonadism and treatment of wasting disorders. While still invaluable therapeutic tools, illicit use of suprapharmacological doses of AAS has overshadowed their clinical use, not only with respect to elite athletes, but also a growing number of "ordinary citizens", and most disturbingly, an appreciable number of adolescents. Chronic AAS use in both human subjects and animal models is associated with marked behavioral changes; the most notable of which are in sexual/reproductive behaviors, aggression and anxiety. Neurotransmission mediated by 7-3minobutyric acid type A (GABAA) receptors in the forebrain plays a crucial role in the expression of all of these behaviors. Interestingly, positive mood symptoms, including euphoria, hypomania and decreased anxiety are also reported, either immediately after exposure or early in the course of AAS use. These effects are reminiscent of the actions of benzodiazepines, ethanol and neurosteroids, and suggest that some of the early positive behavioral manifestations in AAS use may also arise from allosteric modulation of forebrain GABAergic transmission. We have previously shown that chronic AAS treatment alters GABAA receptor expression and function in the basal forebrain in an age- and sex-specific manner. We have also shown that acute AAS administration rapidly alters GABAA receptor function via allosteric modulation and that this modulation depends upon subunit composition. In the current proposal, we will take advantage of a transgenic mouse strain to determine the role of the E subunit in how the AAS alter GABAergic transmission in gonadotropin releasing hormone (GnRH) neurons that control the hypothalamic-pituitary-gonadal axis and are therefore the key regulators of pubertal onset and reproductive maturation. We will take advantage of a specific GABAA receptor subunit knockout strain of mice to determine the role of the a subunits in regulating AAS modulation of neural circuits important for the expression of anxiety. Finally, we will assess how posttranslational modifications of the GABAA receptor regulate allosteric modulation by the AAS and if these changes vary with the age,sex and hormonal state. To these ends we will use whole cell patch clamp recording from acutely isolated brain slices coupled with single cell real time PCR; ultrafast perfusion to recombinant receptors in heterologous cells, and behavioral assessment (ethological elevated plus maze) for anxiolytic effects of the AAS. While the behavioral actions of the AAS are well documented, the underlying neural substrates for these effects are not well known. Our data will generate data important for understanding how these steroids alter neuronal function to produce effects on reproductive and mental health, and how their effects differ in men vs. women and adults vs. children who abuse them. PERFORMANCE SITE ========================================Section End===========================================

超过提供的空间。合成代谢 - 雄激素类固醇（AAS）是用于性降低和治疗浪费障碍的睾丸激素的合成衍生物。尽管仍然宝贵的治疗工具，但非法使用AAS剂量的非法使用量已经掩盖了他们的临床用途，不仅在精英运动员方面，而且越来越多的“普通公民”，而且最令人不安的是，数量可观的青少年。在人类受试者和动物模型中使用慢性AA都与行为变化有明显的变化有关。其中最值得注意的是性/生殖行为，侵略和焦虑。前脑中7-3minobutric Acid A型（GABAA）受体介导的神经传递在所有这些行为的表达中起着至关重要的作用。有趣的是，在暴露后或在AAS使用过程中，还会立即报道阳性情绪症状，包括欣快感，低狂热和焦虑症。这些作用让人联想到苯二氮卓类药物，乙醇和神经类固醇的作用，并暗示AAS使用中某些早期的阳性行为表现也可能来自前脑GABA能传播的变构调节。我们先前已经表明，慢性AAS治疗以年龄和性别特异性的方式改变了基础前脑中GABAA受体的表达和功能。我们还表明，急性AAS给药通过变构调节迅速改变了GABAA受体功能，并且该调节取决于亚基组成。在当前的提案中，我们将利用转基因小鼠菌株来确定E亚基在AAS如何改变促性腺激素释放激素（GNRH）神经元中如何改变GABA能传播的作用，该神经元控制下丘脑 - 丘脑 - 上核 - 核轴的轴，因此是Pubertail ofbertail ofbertal and stset and Prodective Modective moductive merative meration and the。我们将利用小鼠的特定GABAA受体亚基敲除菌株来确定A亚基在调节AAS调节神经回路中的作用，这对于焦虑表达很重要。最后，我们将评估GABAA受体的翻译后修饰如何通过AAS调节变构调节，以及这些变化是否随年龄，性别和激素状态而变化。在这些末端，我们将使用急性分离的脑切片和单细胞实时PCR的全细胞斑块夹记录；对异源细胞中的重组受体的超快灌注，以及对AAS的抗焦虑作用的行为评估（伦理学升高和迷宫）。尽管AAS的行为作用已充分记录，但这些影响的基础神经底物并不众所周知。我们的数据将生成重要的数据，以了解这些类固醇如何改变神经元功能以对生殖和心理健康产生影响，以及它们的影响在男性与妇女与成人与虐待它们的孩子之间的影响。表演站点=============================================================================================